Drug Product Development

Introduction Active pharmaceutical ingredient (API): component that produces pharmacological activity (drug substance).   May b...

Introduction

Active pharmaceutical ingredient (API): component that produces pharmacological activity (drug substance).  May be produced by chemical synthesis, from natural product, enzymatic reaction, recombinant DNA, fermentation, etc. 

New chemical entity (NCE): drug substance with unknown clinical, toxicological, physical, chemical properties.  According to the FDA, NCE is an unapproved API.

Drug product: finished dosage form containing API and excipients. 

Generic drug products: after patent expiration of brand drug.  Therapeutically equivalent to the brand and has the same drug amount in the same dosage form.  Must be bioequivalent (same rate and extent of absorption) à same clinical results.  May differ from brand in excipients (tablets only unless safety studies are done) or physical appearance. 

Abbreviated New Drug Application (ANDA): submitted to the FDA for approval of generic drugs.  Preclinical safety and efficacy studies are not required.  Human bioequivalence is needed (on healthy human volunteers).  Chemistry, manufacturing and controls for generics are similar to the brand.  

Specialty drug products: existing products developed for new delivery system or new therapeutic indication.  Safety and efficacy studies are not required.  Example nitroglycerin transdermal patch after sublignual tablets.

New drug approval

Preclinical (animal safety / pharma) à IND à Phase I (healthy human safety) à Phase II (↓# patients) à Phase III (↑# patients) à NDA à FDA green light for marketing àPhase IV (scale up) à Phase V (continuous improvements). 

Preclinical stage:  animal pharmacology and toxicology to determine safety and efficacy.  Formulation is not final.  

Phase I: Submit an Investigational New Drug (IND) à clinical studies on healthy volunteers to determine toxicity and tolerance.  For oral drugs à simple hard gelatin capsule.  

Phase II: small number of patients under close supervision.  Dose-response studies to determine optimum dosage for treatment.  Determine the therapeutic index (toxic dose/effective dose).  Develop final drug formulation (bioequivalent to that used in initial clinical studies).  Start chronic toxicity studies for 2 years in 2 species. 

Phase III: large-scale multicenter clinical studies with final dosage form (from phase II) to determine safety and efficacy in patients. Watch for new, rare, toxic or side effects. 

NDA submission: FDA satisfaction with safety and efficacy for marketing. 

Phase IV: scale-up in preparation for marketing. Only minor modifications on the formulation are allowed.  

Phase V: continuous drug product improvements after marketing.